Genome-wide mapping of genomic DNA damage: methods and implications

Abstract

Exposures from the external and internal environments lead to the modification of genomic DNA, which is implicated in the cause of numerous diseases, including cancer, cardiovascular, pulmonary and neurodegenerative diseases, together with ageing. However, the precise mechanism(s) linking the presence of damage, to impact upon cellular function and pathogenesis, is far from clear. Genomic location of specific forms of damage is likely to be highly informative in understanding this process, as the impact of downstream events (e.g. mutation, microsatellite instability, altered methylation and gene expression) on cellular function will be positional—events at key locations will have the greatest impact. However, until recently, methods for assessing DNA damage determined the totality of damage in the genomic location, with no positional information. The technique of “mapping DNA adductomics” describes the molecular approaches that map a variety of forms of DNA damage, to specific locations across the nuclear and mitochondrial genomes. We propose that integrated comparison of this information with other genome-wide data, such as mutational hotspots for specific genotoxins, tumour-specific mutation patterns and chromatin organisation and transcriptional activity in non-cancerous lesions (such as nevi), pre-cancerous conditions (such as polyps) and tumours, will improve our understanding of how environmental toxins lead to cancer. Adopting an analogous approach for non-cancer diseases, including the development of genome-wide assays for other cellular outcomes of DNA damage, will improve our understanding of the role of DNA damage in pathogenesis more generally.

Epi-Drugs in Heart Failure

“…In this perspective, it is crucial to head the treatments toward medicine based on one’s genetic composition, disease phenotype, and molecular makeup. A useful tool to identify patients who can benefit from specific drugs is genome mapping ( 23 ). Epigenetic alterations are proven to be restored and epigenetic therapies have arisen.…”

Current and Future Methodology for Quantitation and Site-Specific Mapping the Location of DNA Adducts

“…Further, click chemistry, Click-Code-Seq, has been successfully applied to label 8-oxo-7,8-dihydroguanine (8-oxo-dG) or 5-hydroxymethylcytosine (5hmdC) sites in DNA prior to next-generation sequencing [54,55]. DNA adduct mapping methods have been reviewed extensively [56][57][58].…”

Perspectives on Cyclobutane Pyrimidine Dimers—Rise of the Dark Dimers†

“…Alternatively, the composition of dCPD is reported to contain a higher ratio of cytosine‐containing (T<>C, C<>T) CPD (11) that are more rapidly repaired. Interestingly, this may also correspond to the most frequent mutations seen in nonmelanoma skin cancer (C to T transitions), as repair brings with it an opportunity for mutation (39), and rapid repair may result in decreased fidelity. Finally, an in vitro study in melanocytes suggested that the formation and repair of dCPD may depend on genomic site (40).…”